Resident macrophages isolated from uninfected animals produce large quantities of arachidonic acid (AA) metabolites. Immunizing animals with protein antigens or bacteria activates macrophages and causes an 80% reduction in the cyclooxygenase and lipoxygenase metabolites relative to resident cells. Since some products have been shown to modulate immune functions, we examined how the AA metabolic enzyme activities regulate the products that are synthesized. We demonstrate that the cyclooxygenase, 5-lipoxygenase, prostacyclin synthase, and probably prostaglandin (PG) endoperoxide E-isomerase activities were decreased in activated peritoneal macrophages. In sharp contrast, thromboxane synthase activity was selectively unchanged or enhanced in the activated macrophages. Thus the immune response appears to modulate the activity of the AA and PG endoperoxide-dependent enzymes, thus dictating a major shift in the profile of metabolites synthesized by macrophages.